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Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats

International Journal of Obesity volume 33, pages 601–604 (2009)Cite this article

Abstract

Both 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibition and peroxisome proliferator-activated receptor-γ (PPAR-γ) agonism reduce liver and plasma lipids in rodents through partly distinct mechanisms. This study aimed to assess their additivity of action on liver and plasma lipids in a model of diet-induced steatosis. Rats were fed an obesogenic diet and were treated either with an 11β-HSD1 inhibitor (Compound A, 3 mg kg−1 day−1) or rosiglitazone (RSG, 5 mg kg−1 day−1) or both for 6 weeks. Compound A and RSG reduced liver steatosis and triglyceridemia, and did so additively when given in combination. The 11β-HSD1 inhibitor had no effect on serum adiponectin, but increased liver adiponectin receptor type 2 (Adipo-R2) mRNA levels. Conversely, RSG increased serum adiponectin, a likely mediator of its antisteatotic action, but had no effect per se on the Adipo-R2 expression. mRNA levels of representative genes of fatty acid oxidation tended to be increased by both compounds. The study shows that combined 11β-HSD1 inhibition and PPAR-γ agonism additively reduce liver steatosis and triglyceridemia, which may eventually prove therapeutically useful.

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Acknowledgements

The authors acknowledge the professional assistance of Yves Gélinas, Sébastien Poulin and Josée Lalonde (Laval University), and the contribution of the following personnel from Merck Research Laboratories (Rahway, NJ): Amanda Makarewicz (Medicinal Chemistry) for the preparation of CA, Kathy Lyons (Medicinal Chemistry), Liming Yang and Joseph Metzger (Pharmacology) and Hratch Zokian (Cardiovascular Diseases) for the background work in support of the study. This work was supported by grants from the CIHR and the NSERC (Canada) to YD. Additional support: MB (studentship) and WTF (Postdoctoral Fellowship) from the CIHR-funded Obesity Research Training Program. ML (studentship) from the NSERC.

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Authors and Affiliations

  1. Laval Hospital Research Center and Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Québec, QC, Canada

    M Berthiaume, M Laplante, W T Festuccia & Y Deshaies

  2. Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ, USA

    J P Berger

  3. Department of External Scientific Affairs, Merck Research Laboratories, Rahway, NJ, USA

    R Thieringer

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  1. M Berthiaume
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  2. M Laplante
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  3. W T Festuccia
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  4. J P Berger
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  5. R Thieringer
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  6. Y Deshaies
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Correspondence to Y Deshaies.

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Berthiaume, M., Laplante, M., Festuccia, W. et al. Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats. Int J Obes 33, 601–604 (2009). https://doi.org/10.1038/ijo.2009.33

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